chr12-102855174-T-C
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PM5PP3_Moderate
The NM_000277.3(PAH):āc.668A>Gā(p.Asn223Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000942 in 1,614,070 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N223I) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000277.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PAH | NM_000277.3 | c.668A>G | p.Asn223Ser | missense_variant | 6/13 | ENST00000553106.6 | |
PAH | NM_001354304.2 | c.668A>G | p.Asn223Ser | missense_variant | 7/14 | ||
PAH | XM_017019370.2 | c.668A>G | p.Asn223Ser | missense_variant | 6/7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PAH | ENST00000553106.6 | c.668A>G | p.Asn223Ser | missense_variant | 6/13 | 1 | NM_000277.3 | P1 | |
PAH | ENST00000549111.5 | n.764A>G | non_coding_transcript_exon_variant | 6/6 | 1 | ||||
PAH | ENST00000307000.7 | c.653A>G | p.Asn218Ser | missense_variant | 7/14 | 5 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152220Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251334Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135830
GnomAD4 exome AF: 0.000101 AC: 148AN: 1461850Hom.: 0 Cov.: 34 AF XY: 0.0000990 AC XY: 72AN XY: 727228
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152220Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74368
ClinVar
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 23, 2022 | The c.668A>G (p.N223S) alteration is located in exon 6 (coding exon 6) of the PAH gene. This alteration results from a A to G substitution at nucleotide position 668, causing the asparagine (N) at amino acid position 223 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at